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We present a case of severe rash following induction of elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) in a young adult male cystic fibrosis patient. While rash is a commonly reported side effect which resolves in 1–2 weeks with minimal intervention, our patient had presented with fever and widespread rash prompting medication cessation. After a washout period, reintroduction with 1/2 tablet of ELX/TEZ/IVA produced a similar systemic response within 24 hours. Repeat attempt, this time with 1/8 tablet and increasing in increments of an eighth daily, was successful and has allowed our patient to experience the transformative benefits of ELX/TEZ/IVA including improved pulmonary function and reduced episodes of infective exacerbation. This case illustrates one of the most common side effects of ELX/TEZ/IVA triple therapy, and our experience of desensitisation to ELX/TEZ/IVA in a challenging case of rash.

Neuroinflammation is implicated in the development and maintenance of alcohol use disorder (AUD) and neuroimmune therapeutics show promise in treating AUD. Proinflammatory signaling contributes to progressive elevations in the dysfunction of mood and alcohol craving. The current study sought to examine potential biobehavioral mechanisms of neuroimmune modulation in AUD under experimental conditions. In a community sample of individuals with AUD who completed a placebo-controlled crossover trial of ibudilast, we tested the effect of ibudilast on the relationship between mood states and alcohol craving. Multilevel modeling analyses tested the hypothesis that ibudilast would moderate the effect of positive and negative mood states on alcohol craving during stress and cue exposures. Results revealed that after stress-induction, participants' feelings of depression and happiness were more strongly predictive of their craving for alcohol while taking ibudilast as compared with placebo (

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

Raman spectroscopy provides an extremely high chemical selectivity. Raman difference spectroscopy is a technique to reveal even the smallest differences that occur due to weak interactions between substances and changes in the molecular structure. To enable parallelized and highly sensitive Raman difference spectroscopy in a microtiter-array, a diffractive optical element, a lens array, and a fiber bundle were integrated into a Raman spectroscopy setup in a unique fashion. The setup was evaluated with a microtiter-array containing pyridine-water complexes, and subwavenumber changes below the spectrometer's resolution could be resolved. The spectral changes were emphasized with two-dimensional correlation analysis. Density functional theory calculation and "atoms in molecule" analysis were performed to simulate the intermolecular long-range interactions between water and pyridine molecules and to get insight into the involved noncovalent interactions, respectively. It was found that by the addition of pyridine, the energy portion of hydrogen bonds to the total complexation energy between pyridine and water reduces. These results demonstrate the unique abilities of the new setup to investigate subtle changes due to biochemically important molecular interactions and opens new avenues to perform drug binding assays and to monitor highly parallelized chemical reactions.

An asymmetric catalytic approach for the construction of C3-multifunctionalization α-hydroxy-β-amino pyridines has been reported. The products can be accessed by the modulation of two chiral catalysts independently in high yield and with good enantioselectivity. The method features mild reaction conditions and an excellent functional group tolerance. Biological activity analysis shows that the resulting products have a selective antiosteosarcoma activity on 143B cells.

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

Model-informed dose selection has been drawing increasing interest in oncology early clinical development. The current paper describes the example of FGF401, a selective fibroblast growth factor receptor 4 (FGFR4) inhibitor, in which a comprehensive modeling and simulation (MS) framework, using both pharmacometrics and statistical methods, was established during its first-in-human clinical development using the totality of pharmacokinetics (PK), pharmacodynamic (PD) biomarkers, and safety and efficacy data in patients with cancer. These MS results were used to inform FGF401 dose selection for future development. A two-compartment population PK (PopPK) model with a delayed 0-order absorption and linear elimination adequately described FGF401 PK. Indirect PopPK/PD models including a precursor compartment were independently established for two biomarkers: circulating FGF19 and 7α-hydroxy-4-cholesten-3-one (C4). Model simulations indicated a close-to-maximal PD effect achieved at the clinical exposure range. Time-to-progression was analyzed by Kaplan-Meier method which favored a trough concentration (C

The in vitro antimicrobial activity of Fe(III) and Ga(III) complexes with N'-(2, 3-dihydroxy- phenylmethylidene)-3-pyr- idinecarbohydrazide (H 2 L 1), N'-(2, 4-dihydroxy-phenyl-methylidene)-3- pyridinecarbohydrazide (H 2 L 2), N'-(2, 5-dihy- droxy-phenylmethylidene)-3-pyridinecarbohydrazide (H 2 L 3), N'-(2-hydroxy-3-methoxyphenyl- methylidene)-3-pyri- dine-carbohydrazide (H 2 L 4), N'-(2-hydroxy-4-methoxyphenylmethyl-idene)-3- pyridine-carbohydrazide (H 2 L 5), and N'-(2- hydroxy-5-methoxyphenylmethylidene)-3- pyridinecarbo-hydrazide (H 2 L 6) toward several Gram-positive strains of Staphylococcus aureus, a Gram-negative strain of Escherichia coli, and a yeast Candida albicans were investigated. Fe(III)- complexes do not possess antimicrobial activity against all tested strains at concentrations up to 10 mg mL –1 . Ga(III) com- plexes with dihydroxy derivatives showed selective activity, while the broadest range of antibacterial and antifungal activities was observed for complex with 2- hydroxy-3-methoxy-derivative, ligand H 2 L 5. In addition, the coordination properties of ligands H 2 L 1 –H 2 L 3 in solution were investigated by UV–Vis spectroscopy. The stability constants (logK) for Ga(III)-H 2 L 1:1 complexes in MeOH/H 2 O 1/1 at pH 2.52 were determined, and amounted to 5.8, 5.68, and 4.7, respectively. Detailed characterization of complexes was performed by high-resolution mass spectrometry. The fragmentation pathways for dimer [Fe 2 (L 1) 2 ] 2+ , [Fe(HL) 2 ] + , [Ga(HL 2) 2 ] + and adduct ions are given. The comparison with analogue Ga(III) and Fe(III) com- plexes with compounds H 2 L 4 –H 2 L 6 was made as well.

A mild and eco-friendly visible-light-mediated regioselective C-H alkoxycarbonylation of imidazo[1,2

Fe(II) and Ni(II) paraCEST contrast agents containing the di-pyridine macrocyclic ligand 2,2',2″-(3,7,10-triaza-1,5(2,6)-dipyridinacycloundecaphane-3,7,10-triyl)triacetamide (DETA) are reported here. Both [Fe(DETA)]

A chiral phosphine oxide-ligated Ni-Al bimetallic catalyst was used to realize an enantioselective C2-H alkylation of pyridines without the need of a C2-block. A wide range of pyridines, including unsubstituted pyridine, C3, C4, and C2-substituted pyridines, and even complex pyridine-containing bioactive molecules are well compatible with the reaction, providing up to 81% yield and up to 97% ee.

Epilepsy is a nervous system disease, and seizures are closely related to oxidative stress. Thiols, as the main antioxidant in an organism, play a key role in regulating the redox balance and defending from oxidative stress. As a result of the complexity of the brain structure, there is still a lack of suitableiin/iisitu/idetection methods of thiols to reveal the relationship between epilepsy and thiol level fluctuations. Therefore, by combining picolinate as the new recognition site for thiols, parallel synthesis, and the fluorescence rapid screening method,bDCI-Br-3/bwas developed as a rapid, highly sensitive, and selective probe to monitor thiolsiin/iivitro/iandiin/iivivo/i. It is worth noting thatbDCI-Br-3/beffectively crossed the blood-brain barrier (BBB) to reveal the negative relationship between the level of thiols and the occurrence of epilepsy and may further provide important information for the prevention and treatment of thiol-related neurological diseases.

Filgotinib is an oral Janus kinase type 1 (JAK1) selective inhibitor with demonstrated efficacy and safety in ulcerative colitis (UC). The aim of this review is to summarize the available evidence on pharmacological characteristics, efficacy, and safety of filgotinib in UC.Pubmed, Scopus, and Embase databases were searched for all relevant studies reporting the efficacy and safety of filgotinib in patients with moderate to severe UC. We particularly focused on the risk of zoster infection and venous thromboembolism compared to other JAK inhibitors.Filgotinib has remarkable efficacy, safety, and tolerability profiles in the treatment of moderate-to-severe active UC. It can be used in both biologic-naïve and biologic-experienced patients. The rapid mechanism of action and its oral administration route make it a reliable therapeutic option.

Limited evidence concerning optimal azole dosing regimens currently exists for antifungal prophylaxis in hemato-oncological pediatric patients.Hemato-oncological children receiving intravenous or oral isavuconazole or voriconazole for primary antifungal prophylaxis at IRCCS Azienda Ospedaliero-Universitaria of Bologna during November 2020 to October 2021 and undergoing CPA programs based on real-time therapeutic drug monitoring (TDM) were retrospectively analyzed. CPAs for isavuconazole and voriconazole and the number of dosage adjustments were collected. Normalized trough concentrations [(C min )/dose/kg] were calculated for both drugs at each TDM assessment, and the coefficient of variation was determined. The efficacy and safety of the drugs were evaluated.Sixteen hemato-oncological pediatric patients received azole prophylaxis (mean age and weight: 9.1 ± 4.9 years and 32.6 ± 16.0 kg; 6 isavuconazole and 10 voriconazole). Sixty and 89 CPAs were delivered as isavuconazole and voriconazole, respectively. Dosage adjustments were needed in 3.3% of cases for isavuconazole and 53.9% of cases for voriconazole ( P0.001). At first TDM, achievement of the desired target during standard dosing regimens was higher for isavuconazole (83.3%) than for voriconazole (10.0%; P = 0.008). Dispersion of normalized concentrations was higher for voriconazole (CV = 139.1% vs. CV = 79.4%). Elevation of ALT and aspartate aminotransferase levels between baseline and the third month was higher in patients receiving voriconazole (median, 28 vs. 90 U/L; P = 0.038, and 19 vs. 65.5 U/L; P = 0.002).Our findings suggest that there is limited variability in isavuconazole exposure in hemato-oncological pediatric patients receiving azole prophylaxis , resulting in a low need for CPA-guided dosage adjustments.

The cyclin-dependent kinase (CDK) 4/6 inhibitors, palbociclib and abemaciclib, have been approved in Japan. However, the selection criteria for these drugs have not been established. Hence, we aimed to identify the risk factors for CDK4/6 inhibitor-induced intolerable adverse events requiring dose reduction or therapy cessation and to establish useful markers for choosing the appropriate CDK4/6 inhibitor, based on the incidence of the intolerable adverse events. This retrospective cohort analysis included patients with advanced breast cancer who received 125 mg/d palbociclib or 300 mg/d abemaciclib. We defined significant adverse events (SAEs) as side effects requiring dose reduction or therapy cessation. Thirty-six percent of the patients who received palbociclib (9/25) and 27.3% of those who received abemaciclib (9/33) experienced SAEs. In palbociclib and abemaciclib groups, baseline white blood cell (WBC) counts and serum albumin (ALB) levels, respectively, were significantly lower in patients who experienced SAEs than in those who did not (palbociclib: p = 0.007; abemaciclib: p = 0.004). According to the receiver operating characteristic curve analysis, the optimal cutoff values for baseline WBC count and ALB level were 5700/µL and 4.0 g/dL, respectively. Among patients with ALB levels4.0 g/dL, the incidence of abemaciclib-induced SAEs was significantly lower than that of the palbociclib-induced SAEs (1/17 (5.9%) vs. 6/14 (42.9%), odds ratio: 11.0, 95% confidence interval: 1.07-583, p = 0.0281). Thus, a baseline WBC count ≤5700/µL and ALB level ≤4.0 g/dL may be risk factors for palbociclib and abemaciclib-induced SAEs, respectively. Also, high ALB levels can serve as a useful marker for choosing abemaciclib.

Selpercatinib is a first-in-class, highly selective RET kinase inhibitor with CNS activity that has shown efficacy in RET fusion-positive lung and thyroid cancers. RET fusions occur rarely in other tumour types. We aimed to investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population).LIBRETTO-001 is an ongoing phase 1/2, single-group, open-label, basket trial of selpercatinib in patients aged 18 years and older (or ≥12 years, where permitted by regulatory authorities) with RET-altered cancers. The trial is being conducted at 89 sites in 16 countries; the tumour-agnostic population was enrolled at 30 sites (outpatient and inpatient medical facilities) across eight countries. A prespecified interim analysis of LIBRETTO-001 was planned to investigate the efficacy and safety of selpercatinib in a tumour-agnostic population of patients with RET fusion-positive advanced solid tumours; the data cutoff date was Sept 24, 2021. Eligible patients had disease progression on or after previous systemic therapies or no satisfactory therapeutic options and an Eastern Cooperative Oncology Group performance status of 0-2. Selpercatinib was orally administered in a continuous 28-day cycle. Patients enrolled in the phase 1 dose-escalation portion received between 20 mg once daily or 20-240 mg twice daily; the phase 2 recommended dose was 160 mg twice daily. The primary endpoint was the objective response rate as determined by the independent review committee. The efficacy-evaluable tumour-agnostic population was defined as patients with RET fusion-positive cancer, other than non-small-cell lung cancer and thyroid cancer, who had at least 6 months of follow-up from the first study dose at the time of data cutoff (all responders at the time of data cutoff were followed up for at least 6 months from the onset of response unless they progressed or died earlier). Safety was analysed in the tumour-agnostic population of patients who had been enrolled and received selpercatinib on or before the data cutoff date. This study is registered with ClinicalTrials.gov (NCT03157128) and is still recruiting participants.Between Dec 4, 2017, and Aug 4, 2021, 45 patients with RET fusion-positive tumour-agnostic cancers were enrolled from the phase 1 dose-escalation and phase 2 dose-expansion cohorts of the trial. 43 (96%) of 45 patients received a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. Of the two patients who did not, one received a dose of 160 mg twice daily via intra-patient dose escalation (as allowed per protocol for patients enrolled in the phase 1 portion of the study at lower doses) and the other patient's starting dose of 120 mg twice daily was never escalated. Of the 41 efficacy-evaluable patients, the objective response rate as per the independent review committee was 43·9% (95% CI 28·5-60·3; 18 of 41 patients). The most common grade 3 or worse treatment-emergent adverse events were hypertension (ten [22%] of 45 patients), increased alanine aminotransferase (seven [16%]), and increased aspartate aminotransferase (six [13%]). Treatment-emergent serious adverse events occurred in 18 (40%) of 45 patients. No treatment-related deaths occurred.Selpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib.Loxo Oncology.

ConspectusNearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRAS

Drugs targeting adenosine receptors (AR) can provide treatment for diseases. We report the identification of 7-(phenylamino)-pyrazolo[3,4

To develop and compare benefit-risk profiles for rimegepant, ubrogepant, and lasmiditan based on a network meta-analysis (NMA) of published clinical trials.A fixed-effects Bayesian NMA of randomized controlled trials of lasmiditan, rimegepant, and ubrogepant for the acute treatment of adults with migraine were used to determine risk differences for efficacy and safety outcomes of the 3 treatments compared with pooled placebo. Risk differences were used to calculate number needed to treat (NNT) for pain relief and pain freedom at 2 and 2 to 24 hours and freedom from most bothersome symptoms at 2 hours; and number needed to harm (NNH) for dizziness and nausea, relative to placebo.Results were based on 5 randomized controlled trials (NCT03461757, NCT02828020, NCT02867709, NCT02439320, and NCT02605174). NNT to achieve sustained pain relief at 2 to 24 hours was lowest for rimegepant 75 mg (5; 95% credible interval [Crl]: 4, 7) and ubrogepant 100 mg (5; 95% Crl: 4, 8) and highest for ubrogepant 25 mg (8; 95% Crl: 5, 16). Rimegepant had the lowest NNT to achieve sustained pain freedom at 2 to 24 hours and lasmiditan 50 mg had the highest (7; 95% Crl: 5, 12 vs. 26; 95% Crl: 13, 95). NNH for dizziness and nausea was highest for ubrogepant 25 mg (28; 95% Crl: 15, 62 and 99; 95% Crl: -2580, 2378, respectively). Lasmiditan 200 mg had the lowest NNH for dizziness and rimegepant 75 mg had the lowest NNH for nausea.The benefit-risk profiles of lasmiditan, rimegepant, and ubrogepant may improve clinical decision-making.

2-Amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) was prepared from the reaction of cyclohexane-1,4-dione with elemental sulfur and malononitrile in 1,4-dioxane and triethylamine as catalyst. The latter compound reacted with triethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce 4H-thieno[2,3-f]chromene derivatives 10a,b. In addition, fused pyran and pyridine derivatives were synthesized starting from compound 3. The cytotoxicities of the synthesized compounds were studied using the six cancer cell lines together with c-Met kinase and PC-3 cell line. The most active compounds were tested against five tyrosine kinases and Pim-1 kinase, most of which showed strong inhibition, encouraging further work.

Sulfoxaflor is a new systemic insecticide developed as a replacement for older neonicotinoids which are known to be toxic to pollinators. However, its metabolism in nectar and effect on nectar biosynthesis have not been investigated. After soil and foliar application, sulfoxaflor and its main metabolites in soil, leaf and Salvia splendens nectar, were measured by liquid chromatography coupled with triple quadrupole mass spectrometer (LC-MS/MS). The chemical composition between the clean and sulfoxaflor spiked nectar were also compared. The activities of two possible sulfoxaflor detoxifying enzymes in S. splendens nectar, nitrile hydratase and glutathione-s-transferase, were measured by LC-MS and spectrophotometry. S. splendens nectar proteome was investigated by high-resolution orbitrap-based MS/MS to screen for sulfoxaflor detoxifying relevant proteins. S. splendens could absorb sulfoxaflor through root or leaf surface and secrete a proportion of sulfoxaflor along with its metabolites into the nectar. After soil application, sulfoxaflor's low toxic metabolite X11719474 was dominant in the nectar and reached an average concentration of 8905 ppb. However, after foliar application, sulfoxaflor was dominant over its metabolites in the nectar. S. splendens nectar has no nitrile hydratase and glutathione-s-transferase activity and none of the 106 proteins identified in the nectar were predicted to function in detoxifying sulfoxaflor. Soil and foliar sulfoxaflor application can result in different profiles of sulfoxaflor and its metabolites presented in the nectar. However, sulfoxaflor had no effects on S. splendens nectar secretion and chemical composition and cannot be directly detoxified by components in the nectar.

Objective. To systematically evaluate the clinical efficacy and safety of karelizumab combined with apatinib in the treatment of advanced gastric cancer. Methods. The published databases were searched by computer, Chinese: China Biomedical Literature Database (CBM), Wanfang Journal Database, China national knowledge infrastructure (CNKI), and China Science and Technology Journal Database (VIP); English: Embase, Cochrane library, and PubMed. The search time is from the establishment of the database to May 2022, and clinical randomized controlled trials (RCT) with advanced gastric cancer as the research object and karelizumab combined with apatinib as the research variables are collected. According to the bias risk evaluation standard of Cochrane System Evaluator’s Manual, the literatures meeting the inclusion standard were evaluated for bias risk, and the meta-analysis was conducted by Review Manager 5.3. Results. A total of 20 articles with 1150 patients were included in this study. All the included 20 articles reported objective remission rate (ORR), and the heterogeneity among 20 studies was low ( P > 0.05 , I 2 = 0 %). The ORR of gastric cancer patients in the observation group was significantly higher than that in the blank group [odds ratio OR = 1.97 , 95% CI [1.53, 2.62], P < 0.01 ). All the included 20 articles reported disease control rate (DCR), and the heterogeneity among 20 studies was low ( P = 0.87 , I 2 = 0 %). The ORR of gastric cancer patients in the observation group was significantly higher than that in the blank group ( OR = 3.09 , 95% CI [2.29, 4.16], P < 0.01 ). Three articles in the included literature reported the median OS, and the heterogeneity among the three studies was low ( P = 0.70 , I 2 = 0 %). The median OS of gastric cancer patients in the observation group was significantly higher than that in the blank group ( MD = 3.97 , 95% CI [3.61, 4.39], P < 0.01 ). There are three reports on median progression-free survival (PFS) in the included literature, and there is high homogeneity among the three studies ( P < 0.00001 , I 2 = 86 %). There is no statistical difference between the median PFS of gastric cancer patients in the observation group and the blank group ( MD = 1.21 , 95% CI [−1.20, 3.70], P = 0.29 ). The incidence of hypertension in the observation group was significantly higher than that in the blank group [ OR = 6.19 , 95% CI (1.91, 20.20), P = 0.003 ]. The incidence of proteinuria in the observation group was significantly higher than that in the blank group [ OR = 3.97 , 95% CI (1.08, 14.59), P = 0.03 ]. There was no significant difference in the incidence of other adverse reactions such as hand-foot syndrome, diarrhea, and myelosuppression between the observation group and the blank group. The levels of IFN-γ and TNF-α in the observation group were significantly higher than those in the blank group ( P < 0.0001 ). The levels of IL-10, IL-4, and tumor markers in the observation group were significantly lower than those in the blank group ( P < 0.05 ). Egger’s test showed that there was no publication bias in the 20 included studies ( P > 0.05 ). Conclusion. Karelizumab combined with apatinib is effective in the treatment of advanced gastric cancer, with low incidence of adverse reactions and high safety. However, a large number of multicenter, large sample size, and high-level RCT are needed for clinical verification.

A longstanding challenge in fundamental functional group interconversion has been the direct transformation of benzene into pyridine via nitrogen insertion and carbon deletion. Herein, we report a protocol for the transformation of aryl azides, easily accessible from their corresponding anilines, to 2-aminopyridines using blue light and oxygen. Mechanistic studies corroborate that the arene to pyridine conversion is achieved by nitrogen insertion into the benzene ring followed by oxidative carbon extrusion.

Venous thromboembolism (VTE) is a common complication in patients hospitalized for acute medical illnesses. Therefore, medical inpatients require a careful VTE and bleeding risk assessment to drive optimal strategies for VTE prevention. Low molecular weight heparin and fondaparinux have long been used for inhospital prophylaxis for patients at increased risk of VTE. The selection of patients who require post-discharge prophylaxis, and the role of direct oral anticoagulants remain debated. New molecules currently under development may contribute to improve the risk benefit of VTE prevention in this setting.This text summarizes the evidence on approved treatments and on other drugs for the prevention of VTE in acutely ill medical patients. The main focus is on their pharmacological properties, clinical efficacy and safety, and the current license approved by the FDA (Food and Drug Administration) and EMA (European Medicines Agency). The trials presented consider both inhospital and extended prophylaxis.Thanks to the potentially favorable safety profile, factor XI inhibitors may play a role in the prevention of VTE in this setting. The expert opinion section discusses pharmacological properties, prophylaxis trials, and potential clinical applications of this novel class of drugs.

Lasmiditan is the first 5-HTPatients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.NCT03670810.Although there is significant unmet medical need among patients with migraine, there has been no novel compound for treatment of migraine over past two decades in China. These unmet medical needs persist because the current available medications for the acute treatment of migraine are reported to have safety and tolerability issues. Lasmiditan is a new class of acute migraine medication (5-HT receptor agonist with high selectivity for the 5-HT

Polar and polarizable π-conjugated organic molecules containing push-pull chromophores have been investigated extensively in the past. Identifying unique backbones and building blocks for fluorescent dyes is a timely exercise. Here, we report the synthesis and characterization of a series of fluorescent dyes containing quadrupolar A-D-A constitutions (where A = acceptor and D = donor), which exhibit fluorescence emission at a variety of different wavelengths. We have investigated the effects of different electron-withdrawing groups, located at both termini of a

Chemodivergent synthetic methodologies enable the efficient introduction of structural diversity into high-value organic products via simple chemical alterations. In this regard, C-H activation and functionalization of pyridinoid azines are important transformations in the synthesis of many natural products, pharmaceuticals, and functional materials. Reflecting on azinyl nitrogen lone-pair steric repulsion, its tendency to irreversibly coordinate metal ion catalysts, and the electron deficiency of pyridine, C-H functionalization at the important α-position remains challenging. Thus, developing earth-abundant catalysts for α-selective azine mono-functionalization is an attractive target for chemical synthesis. Here, the selective organolanthanide-catalyzed α-mono-borylation of a diverse series of 18 pyridines is reported using Cp*

Background: Intracerebral translocator protein 18 kDa (TSPO) mediates the transport of cholesterol from cytoplasm to mitochondria and activation of microglia. The change of TSPO and the dysfunction of microglia are closely related to the pathogenesis of Alzheimer’s disease (AD). Aims: This study aimed to investigate the effects of microglial TSPO and its selective ligand YL-IPA08 on the cognitive function of transgenic mice in 5 × familial Alzheimer’s disease (FAD) mouse model of AD. Methods: The TSPO knockout 5 × FAD transgenic mice were bred, and tested by Morris water maze. The effects of YL-IPA08 on cognitive abilities and expression of Aβ in 5 × FAD mice were also explored into. Results: The latency of escape by TSPO knockout 5 × FAD mice was significantly prolonged compared with the 5 × FAD group, indicating that the cognitive impairment of mice aggravated. With the attenuated phagocytic ability of microglia, the deposition of Aβ in prefrontal cortex of TSPO knockout 5 × FAD mice increased, and the expression of proinflammatory factors (IL-1β, TNF-α, IL-6) were upregulated. In addition, YL-IPA08 significantly reduced the latency of escape by 5 × FAD mice, increased the number of times of crossing over the platform by mice, and inhibited the deposition of Aβ in the prefrontal cortex of 5 × FAD mice without affecting the cleavage of APP. Conclusion: Our findings suggested that TSPO knockout in 5 × FAD mice inhibited microglial phagocytosis, promoted Aβ deposition and neuroinflammation, and aggravated cognitive dysfunction in AD mice. YL-IPA08 had a significant cognition-enhancing effect in 5 × FAD transgenic mice, which might provide a new basis for potential drug candidates in AD treatment.

In this work, a series of derivatives with disulfide bonds containing pyridine, pyrimidine, thiophene, thiazole, benzothiazole, and quinoline were designed and synthesized based on the various biological activities of allicin disulfide bond functional groups. The antimicrobial activities of the target compounds were determined, and the structure-activity relationships were discussed. Among them, compound

Clostridium (Clostridioides) difficile infection (CDI) remains an urgent threat to patients in health systems worldwide. Recurrent CDI occurs in up to 30% of cases due to sustained dysbiosis of the gut microbiota which normally protects against CDI. Associated costs of initial and recurrent episodes of CDI impose heavy financial burdens on health systems. Vancomycin and metronidazole have been the mainstay of therapy for CDI for many years; however, these agents continue to cause significant disruption to the gut microbiota and thus carry a high risk of recurrence for CDI patients. Treatment regimens are now turning towards novel narrow spectrum antimicrobial agents which target C. difficile while conserving the commensal gut microbiota, thus significantly reducing risk of recurrence. One such agent, fidaxomicin, has been in therapeutic use for several years and is now recommended as a first-line treatment for CDI, as it is superior to vancomycin in reducing risk of recurrence. Another narrow spectrum agent, ridnilazole, was recently developed and is undergoing evaluation of its potential clinical utility. This review aimed to summarize experimental reports of ridinilazole and assess its potential as a first-line agent for treatment of CDI. Reported results from in vitro assessments, and from hamster models of CDI, show potent activity against C. difficile, non-inferiority to vancomycin for clinical cure and non-susceptibility among most gut commensal bacteria. Phase I and II clinical trials have been completed with ridinilazole showing high tolerability and efficacy in treatment of CDI, and superiority over vancomycin in reducing recurrence of CDI within 30 days of treatment completion. Phase III trials are currently underway, the results of which may prove its potential to reduce recurrent CDI and lessen the heavy health and financial burden C. difficile imposes on patients and healthcare systems.

Abstract: Pyridine derivatives are the most common and significant heterocyclic compounds, which show their fundamental characteristics to various pharmaceutical agents and natural products. Pyridine derivatives possess several pharmacological properties and a broad degree of structural diversity that is most valuable for exploring novel therapeutic agents. These compounds have an extensive range of biological activities such as antifungal, antibacterial, anticancer, anti-obesity, anti-inflammatory, antitubercular, antihypertensive, antineuropathic, antihistaminic, antiviral activities, and antiparasitic. The potent therapeutic properties of pyridine derivatives allow medicinal chemists to synthesize novel and effective chemotherapeutic agents. Consequently, the imperative objective of this comprehensive review is to summarize and investigate the literature regarding recent advancements in pyridine-based heterocycles to treat several kinds of cancer. Furthermore, the performances of pyridine derivatives were compared with some standard drugs, including etoposide, sorafenib, cisplatin, and triclosan, against different cancer cell lines. We hope this study will support the new thoughts to pursue the most active and less toxic rational designs.

Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.

Masitinib is a small molecule tyrosine kinase inhibitor under investigation for the treatment of amyotrophic lateral sclerosis, mastocytosis, and COVID-19. Hepatotoxicity has been reported in some patients while taking masitinib. The liver injury is thought to involve hepatic metabolism of masitinib by cytochrome P450 (P450) enzymes to form chemically reactive, potentially toxic metabolites. The goal of the current investigation was to determine the P450 enzymes involved in the metabolic activation of masitinib in vitro. In initial studies, masitinib (30 μM) was incubated with pooled human liver microsomes in the presence of NADPH and potassium cyanide to trap reactive iminium ion metabolites as cyano adducts. Masitinib metabolites and cyano adducts were analyzed using reversed-phase liquid chromatography–tandem mass spectrometry. The primary active metabolite, N-desmethyl masitinib (M485), and several oxygenated metabolites were detected along with four reactive metabolite cyano adducts (MCN510, MCN524, MCN526, and MCN538). To determine which P450 enzymes were involved in metabolite formation; reaction phenotyping experiments were conducted by incubation of masitinib (2 μM) with a panel of recombinant human P450 enzymes and by incubation of masitinib with human liver microsomes in the presence of P450-selective chemical inhibitors. In addition, enzyme kinetic assays were conducted to determine the relative kinetic parameters (apparent [Formula: see text] and [Formula: see text]) of masitinib metabolism and cyano adduct formation. Integrated analysis of the results from these experiments indicates that masitinib metabolic activation is catalyzed primarily by P450 3A4 and 2C8, with minor contributions from P450 3A5 and 2D6. These findings provide further insight into the pathways involved in the generation of reactive, potentially toxic metabolites of masitinib. Future studies are needed to evaluate the impact of masitinib metabolism on the toxicity of the drug in vivo.

Anticancer drugs confront clinical obstacles such as drug resistance and adverse effects. Imidazo[1,2-a]pyridines (IPs) compounds have lately gained considerable interest as possible anticancer therapeutics due to their potent inhibitory function against cancers cells. This study was to determine the anticancer activities of three novel IPs (IP-5, IP-6, and IP-7) against the HCC1937 breast cancer cell line in vitro.The cytotoxic and anti-proliferative effects of IPs compounds in HCC1937 cells were determined by cell viability (MTT) assay, trypan blue assay, and clonogenic survival assay. Scratch motility assay was used to test the antimigration ability of the IPs. Western blot analysis was carried out to detect the level of apoptosis and cell cycle protein markers and to understand the mechanism of action of IPs compounds.IP-5 and IP-6 have a strong cytotoxic impact against HCC1937 cells with IC50 values of 45µM and 47.7µM respectively. IP-7 possesses less cytotoxic effect against HCC1937 cells with IC50 of 79.6µM. Trypan blue assay showed that the three compounds induce significant cell death in the HCC1937 cells. Clonogenic and mammosphere assays demonstrated that IP-5 reduced the HCC1937 cells survival rate by more than 25.0% at 1000 cell concentrations. Western blotting analysis showed that IP-5 compound causes cell cycle arrest as noted by the increasing levels of p53 and p21 in treated cells. IP-5 induced an extrinsic apoptosis pathway as reveals from the increased activity of caspase 7, caspase 8, and the increasing level of PARP cleavage in treated cells. Also, IP-5 treated cells revealed segmented chromatin which is characteristic of apoptotic cells as shown by DAPI stain. Importantly, In comparison to control cells, IP-5-treated cells exhibited lower levels of pAKT.The novel three IPs compounds represent potential active anticancer compounds against HCC1937 breast cancer cells in vitro.

The results of the phase III ClarIDHy trial have led to US FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations.In this study, we report the first real-world experience including eight patients with previously treated locally advanced or metastatic IDH1-mutated CCA treated with ivosidenib.Patients treated with ivosidenib as second and third line for advanced CCA were collected with the aim of evaluating the survival outcomes. A molecular study has been performed by next-generation sequencing assay.After a median follow up of 9.4 months, median progression-free survival (PFS) from the start of treatment with ivosidenib was 4.4 months (95% confidence interval [CI] 3.3-5.8), whereas median overall survival (OS) was not reached. The disease control rate was 62.5%, with two patients achieving a partial response (25%); 12.5% of patients experienced a treatment-related adverse event (AE), but no grade 3 or higher AEs were reported. The observed grade 2 AEs were prolonged QT interval and hypomagnesemia (25% of the sample). Molecular profiling was performed on six of eight patients, highlighting TP53, BAP1, CDKN2A and CDKN2B as the most common co-altered genes in these patients.Efficacy outcomes were consistent with those reported in the ClarIDHy trial. Real-world experiences on larger samples are needed in order to confirm our results.

Although several studies have compared the effectiveness and safety of rivaroxaban and apixaban in patients with venous thromboembolism (VTE), direct comparison of these drugs with edoxaban is lacking.We compared the effectiveness and safety of edoxaban, rivaroxaban, and apixaban in patients with VTE.In this retrospective cohort study using a Japanese hospital administrative database, we identified three mutually exclusive groups of patients with VTE beginning treatment with edoxaban, rivaroxaban, or apixaban. Primary effectiveness outcome was recurrent VTE, and principal safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding. Subjects were followed for up to 180 days. Baseline characteristics among groups were balanced using propensity score matching weights.Three thousand three hundred sixty-nine edoxaban, 1592 rivaroxaban, and 1998 apixaban initiators were identified. There were no significant differences among the three drugs in the prevention of recurrent VTE (adjusted incidence rate ratio [aIRR], 0.77; 95% confidence interval [CI], 0.45-1.30 for edoxaban vs. rivaroxaban; aIRR, 0.92; 95% CI, 0.54-1.56 for edoxaban vs. apixaban; and aIRR, 1.20; 95% CI, 0.69-2.10 for rivaroxaban vs. apixaban), or in the risk of intracranial hemorrhage or gastrointestinal bleeding (aIRR, 1.57, 95% CI, 0.85-2.90 for edoxaban vs. rivaroxaban; aIRR, 1.30, 95% CI, 0.76-2.23 for edoxaban vs. apixaban; and aIRR, 0.83, 95% CI, 0.42-1.64 for rivaroxaban vs. apixaban).In routine care, edoxaban, rivaroxaban, and apixaban appear to have similar effectiveness and safety in the treatment of VTE.

Dimethyl sulfate is an important chemical raw material that is widely used in the synthesis of drugs, dyes, spices, and pesticides. The highly toxic and corrosive dimethyl sulfate residue in medicines is harmful to the human body, and hence, the residue level should be strictly controlled. Traditional detection methods use high-purity acetonitrile and anhydrous as the solvents, which limits the choice of detection solvents and degrades the versatility and accuracy of detection. Therefore, a simple and accurate method for the determination of dimethyl sulfate residues is urgently needed. Dimethyl sulfate is usually detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with pyridine as the methylation substrate. In this study, a new method for the detection of dimethyl sulfate was established using tertiary amines such as aminophenazone, which has many advantages over pyridine, as the methylation substrate. For example, the hybrid orbital and electron cloud of the N atom are different, resulting in stronger nucleophilicity of aminophenazone. High temperatures that are detrimental to the stability of dimethyl sulfate are not required when using aminophenazone, and the aliphatic quaternary ammonium salt product is more stable, with good stability, low interference, good ionization properties, and high response. The separation was performed on a Waters Atlantis HILIC C18 column (100 mm×2.1 mm, 3.0 μm) using a mobile phase consisting of 10 mmol/L ammonium acetate solution-0.1% formic acid methanol solution (50∶50, v/v) at a flow rate of 0.3 mL/min. The column temperature was set at 40 ℃, and the sample size was 1 μL. Dimethyl sulfate was determined in the electrospray positive ionization (ESI

ConspectusAsymmetric organocatalysis has been considered to be an efficient and reliable strategy for the stereoselective preparation of optically active chemicals. In particular, chiral tertiary amines as Lewis base organocatalysts bearing core structures including quinuclidine, dimethylaminopyridine (DMAP)

We report a joint experimental-theoretical study of the never reported before structure and infrared spectra of gas phase monohydrated nicotine (NIC) and nornicotine (NOR) and use them to assign their protonation sites. NIC's biological activity is strongly affected by its protonation site, namely, the pyrrolidine (Pyrro-NICH

N´-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) – which always occur together and are present exclusively in tobacco products – are classified as “carcinogenic to humans” (Group 1) by the International Agency for Research on Cancer. While 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) serves as an excellent biomarker for NNK exposure, the currently available biomarker for NNN exposure is urinary “total NNN” (free NNN plus its N-glucuronide). Quantitation of urinary NNN requires extensive precautions to prevent artifactual formation of NNN resulting from nitrosation of nornicotine during analysis. NNN itself can also be formed endogenously by the same nitrosation reaction which may sometimes cause overestimation of exposure to preformed NNN. It is thus important to develop an alternative biomarker to specifically reflect NNN metabolic fate and facilitate relevant cancer etiology studies. In this study, we report the first detection of N´-nitrosonornicotine-1N-oxide (NNN-N-oxide) in human urine. Using a highly specific and sensitive MS(3) transition-based method, NNN-N-oxide was quantified with a mean level of 8.40 ± 6.04 fmol/mL in the urine of 10 out of 32 cigarette smokers. It occurred in a substantially higher level in the urine of 13 out of 14 smokeless tobacco users, amounting to a mean concentration of 85.2 ± 96.3 fmol/mL urine. No NNN-N-oxide was detected in any of the non-smoker urine samples analyzed (n = 20). The possible artifactual formation of NNN-N-oxide during sample preparation steps was excluded by experiments using added ammonium sulfamate. The low levels of NNN-N-oxide in the urine of tobacco users indicate that the pyridine N-oxidation pathway represents a minor detoxification pathway of NNN, which further supports the importance of the α-hydroxylation pathway of NNN metabolic activation in humans.

(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant

A wide range of functionalized pyridine ligands have been employed to synthesize a variety of Pd(II) complexes of the general formulas [Pd

The heterogeneity and aggressiveness of triple-negative breast cancer (TNBC) contribute to its early recurrence and metastasis. Despite substantial research to identify effective therapeutic targets, TNBC remains elusive in terms of improving patient outcomes. Here, we report that a covalent JNK inhibitor, JNK-IN-8, suppresses TNBC growth both in vitro and in vivo. JNK-IN-8 reduced colony formation, cell viability, and organoid growth in vitro and slowed patient-derived xenograft and syngeneic tumor growth in vivo. Cells treated with JNK-IN-8 exhibited large, cytoplasmic vacuoles with lysosomal markers. To examine the molecular mechanism of this phenotype, we looked at the master regulators of lysosome biogenesis and autophagy transcription factor EB (TFEB) and TFE3. JNK-IN-8 inhibited TFEB phosphorylation and induced nuclear translocation of unphosphorylated TFEB and TFE3. This was accompanied by an upregulation of TFEB/TFE3 target genes associated with lysosome biogenesis and autophagy. Depletion of both TFEB and TFE3 diminished the JNK-IN-8–driven upregulation of lysosome biogenesis and/or autophagy markers. TFEB and TFE3 are phosphorylated by a number of kinases, including mTOR. JNK-IN-8 reduced phosphorylation of mTOR targets in a concentration-dependent manner. Knockout of JNK1 and/or JNK2 had no impact on TFEB/TFE3 activation or mTOR inhibition by JNK-IN-8 but inhibited colony formation. Similarly, reexpression of either wildtype or drug-nonbinding JNK (C116S) in JNK knockout cells did not reverse JNK-IN-8–induced TFEB dephosphorylation. In summary, JNK-IN-8 induced lysosome biogenesis and autophagy by activating TFEB/TFE3 via mTOR inhibition independently of JNK. Together, these findings demonstrate the efficacy of JNK-IN-8 as a targeted therapy for TNBC and reveal its novel lysosome- and autophagy-mediated mechanism of action.

We report a method for the synthesis of carbamoyl fluorides from secondary amines using bench-stable, inexpensive, and readily accessible starting materials that, when combined, yield a surrogate for toxic difluorophosgene (COF

Undesirable activation of endosomal toll-like receptors TLR7 and TLR9 present in specific immune cells in response to host-derived ligands is implicated in several autoimmune diseases and other contexts of autoreactive inflammation, making them important therapeutic targets. We report a drug development strategy identifying a new chemotype for incorporating relevant structural subunits into the basic imidazopyridine core deemed necessary for potent TLR7 and TLR9 dual antagonism. We established minimal pharmacophoric features in the core followed by hit-to-lead optimization, guided by in vitro and in vivo biological assays and ADME. A ligand-receptor binding hypothesis was proposed, and selectivity studies against TLR8 were performed. Oral absorption and efficacy of lead candidate

Background Verinurad is a human uric acid (UA) transporter (URAT1) inhibitor known to decrease serum UA (sUA) levels and that may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval 4–62%) among patients with Type 2 diabetes mellitus, hyperuricaemia and albuminuria. The Phase 2b, randomized, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicaEmia (SAPPHIRE; NCT03990363) will examine the effect of verinurad + allopurinol on albuminuria and estimated glomerular filtration rate (eGFR) slope among patients with chronic kidney disease (CKD) and hyperuricaemia. Methods Adults (≥18 years of age) with CKD, eGFR ≥25 mL/min/1.73 m2, UACR 30–5000 mg/g and sUA ≥6.0 mg/dL will be enrolled. Approximately 725 patients will be randomized 1:1:1:1:1 to 12, 7.5 or 3 mg verinurad + allopurinol, allopurinol or placebo. An 8-week dose-titration period will precede a 12-month treatment period; verinurad dose will be increased to 24 mg at Month 9 in a subset of patients in the 3 mg verinurad + allopurinol arm. The primary efficacy endpoint the is change from baseline in UACR at 6 months. Secondary efficacy endpoints include changes in UACR, eGFR and sUA from baseline at 6 and 12 months. Conclusions This study will assess the combined clinical effect of verinurad + allopurinol on kidney function in patients with CKD, hyperuricaemia and albuminuria, and whether this combination confers renoprotection beyond standard-of-care.

Background: It is unknown whether the direct oral anticoagulant edoxaban can reduce leaflet thrombosis and the accompanying cerebral thromboembolic risk after transcatheter aortic valve replacement. In addition, the causal relationship of subclinical leaflet thrombosis with cerebral thromboembolism and neurological or neurocognitive dysfunction remains unclear. Methods: We conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy (aspirin plus clopidogrel) in patients who had undergone successful transcatheter aortic valve replacement and did not have an indication for anticoagulation. The primary end point was an incidence of leaflet thrombosis on 4-dimensional computed tomography at 6 months. Key secondary end points were the number and volume of new cerebral lesions on brain magnetic resonance imaging and the serial changes of neurological and neurocognitive function between 6 months and immediately after transcatheter aortic valve replacement. Results: A total of 229 patients were included in the final intention-to-treat population. There was a trend toward a lower incidence of leaflet thrombosis in the edoxaban group compared with the dual antiplatelet therapy group (9.8% versus 18.4%; absolute difference, −8.5% [95% CI, −17.8% to 0.8%]; P =0.076). The percentage of patients with new cerebral lesions on brain magnetic resonance imaging (edoxaban versus dual antiplatelet therapy, 25.0% versus 20.2%; difference, 4.8%; 95% CI, −6.4% to 16.0%) and median total new lesion number and volume were not different between the 2 groups. In addition, the percentages of patients with worsening of neurological and neurocognitive function were not different between the groups. The incidence of any or major bleeding events was not different between the 2 groups. We found no significant association between the presence or extent of leaflet thrombosis with new cerebral lesions and a change of neurological or neurocognitive function. Conclusions: In patients without an indication for long-term anticoagulation after successful transcatheter aortic valve replacement, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effects on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the 2 groups. Because the study was underpowered, the results should be considered hypothesis generating, highlighting the need for further research. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03284827.